首页 > 资讯 > FDA新版批准前检查手册精华导读 I：商业化生产准备就绪的5项检查目标和要点详述

出自识林

2019-09-06

2019年8月13日，FDA发布了新版《批准前检查手册》（CPGM 7346.832 Pre-Approval Inspections-Investigations），合规项目指南手册（Compliance Program Guidance Manual，CPGM）为 FDA 人员评价企业合规性活动时提供指导，是FDA指导检查员的工作手册，其中包含了对FDA检查员执行检查的细致考虑和要求，是企业知己知彼，学习提高的好资料。

新版的批准前检查手册将于2019年9月16日实施，对比9年前（2010年5月12日）的版本，除了法规、技术要求等大量与时俱进的细节修订，还有三点突出变化：

1. 新版手册不再覆盖生物制品的批准前检查，相关要求应参考《7356.002M 生物治疗产品检查》和《7356.002A 无菌产品工艺检查》以及21 CFR 210, 211, 600, 和 610（请登录识林搜索“CPGM”查看更多检查手册及中文翻译）。

2. 体现了FDA项目整合和机构改革的变化，明确了工艺和设施办公室（Office of Process and Facilities, OPF）和药品质量办公室（Office of Pharmaceutical Quality, OPQ）等新机构的在批准前检查中的职能，及其和监管事务办公室（Office of Regulatory Affairs, ORA）的新工作机制。

3. 基于风险的监管理念更加成熟，删去了旧版的检查优先级决策树和建议，介绍了通过新的整合信息化平台 Panorama 管理检查和沟通风险。

识林将对手册中的精华内容展开系列化介绍，批准前检查有三大目标：(1) 商业化生产是否准备就绪，(2) 与申请材料的一致性以及 (3) 数据可靠性，本文介绍第一个目标 — 商业化生产准备就绪的5项检查目标和技术细节。

Objective 1: Readiness for Commercial Manufacturing

目标1：为商业化生产准备就绪

Determine whether the establishment has a quality system that is designed to achieve sufficient control over the facility and commercial manufacturing operations.

确定企业的质量体系是否足以实现对生产设施和商业化生产操作的充分控制。

(a) Objective 1a: Manufacturing and laboratory changes, deviations, and trends relating to the development of drug substance and drug product manufacturing have been adequately evaluated.

(a) 目标 1a: 与原料药及制剂生产研发相关的生产与实验室方面的变更，偏差，以及趋势分析都已进行了充分的评估。

Assess whether investigations relevant to the proposed commercial manufacturing process have been appropriately evaluated, including related laboratory, equipment maintenance, and manufacturing (e.g., development batch) investigations. Investigative reports or resultant change control reports for development issues may not always be as comprehensive as required for marketed drugs. Nonetheless, the firm should appropriately document, record, and objectively assess all development data and information, including but not limited to data submitted in or generated after the filing of an application or DMF. Examples of deviations related to the application include:

要确认企业对生成商业批生产方案所作的相关调查经过了适当的评估，包括相关实验室调查，设备维护调查，以及相关生产（比如研发批次）调查。对研发过程中出现问题的调研性报告或者因此产生的变更控制报告不需要像已上市药品所要求的那样复杂。尽管如此，企业仍需生成适当的文件并记录，以及客观的评价所有的研发数据和信息，包括但不限于申请中用到的数据或者是申请提交后生成的数据。与申报相关的偏差举例如下：

• Laboratory issues that occurred during or after method validation, such as:

o Unexpected laboratory events—including results that fall outside of the specifications or acceptance criteria—identified during stability, in-process, and release testing for the exhibit batches, biobatches, or process validation batches.

o Discrepancies found while conducting the method validation (particularly issues that may have occurred in its final stages) or technical transfer.

o Changes in an analytical method after completing the method validation or technical transfer because of an inability to use the method as written.

• 方法验证期间或者是之后出现的实验室问题，比如：

o意外的实验室事件 - 包括超出质量标准或可接受标准的结果 - 在展示批，生物批或工艺验证批的稳定性，中间过程和放行检验中发现的。

o 在进行方法验证（特别是在最后阶段可能发生的问题）或者技术转移时发现的差异

o 因为事先编写的方法无法使用，而在分析方法验证或技术转移结束后发生的变更

• Related equipment maintenance and performance issues, which could affect the proposed commercial manufacturing process, such as:

o Calibration failures associated with commercial equipment planned for use in the proposed commercial batch record.

o CGMP investigations and trending associated with the performance and capability of the commercial equipment planned for use in the proposed commercial batch record.

o CGMP manufacturing investigations (e.g., significant deviations, rejects, complaints/returns) and trending associated with similarly manufactured marketed drug products at the establishment.

o Significant equipment failures.

• 可能影响商业批生产的相关设备的维护和设备性能问题，比如：

o 与计划用于商业批记录的商业化设备相关的校准失败。

o 对计划用于商业批生产记录的设备性能及能力相关的CGMP调查和趋势分析

o 对该企业已上市药品类似生产中相关的 CGMP 生产调查（比如，重大偏差，拒收，投诉/退货），以及趋势分析。

o 严重的设备故障。

Evaluate these investigations to determine if the establishment is prepared for the proposed commercial manufacturing process at commercial scale, including that there are appropriate controls in place to detect and mitigate the most likely and significant problems.

对这些调查进行评估，确定该企业是否对提交的商业化批次规模下的生产工艺做好了准备，并且具有相应的控制程序去发现和避免最可能发生且重大的问题。

Related regulations for finished pharmaceuticals: 21 CFR 211.67(a) addresses equipment maintenance, cleaning, and sanitization. For the validation/verification of analytical methods, refer to CFR 211.160–211.167 and 211.194. Refer to 21 CFR 211.100, 211.192, and 211.198 for regulations relating to product deviations and investigations.

制剂的相关法规：制剂成品相关法规：21 CFR 211.67(a) 针对设备维护，清洁和消毒。关于分析方法验证/确认请参见CFR 211.160–211.167 和 211.194。关于产品偏差及调查相关法规请参见21 CFR 211.100, 211.192, 和 211.198。

Related guidance for APIs: For preventative maintenance, cleaning, and sanitization of equipment, refer to International Council for Harmonisation (ICH) guidance for industry Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients, section V.B, Equipment Maintenance and Cleaning. For the validation of analytical methods, refer to ICH Q7, section XII.H, Validation of Analytical Methods. For guidance relating to product investigations, refer to ICH Q7, sections VI.E, Batch Production Records, VI.G, Batch Production Record Review, VIII.A, Production Operations, and XV, Complaints and Recalls.

API的相关指南：关于设备的预防性维护，清洁和消毒，参见ICH行业指南Q7 5.2部分，设备维护和清洁。针对分析方法验证的要求，参见ICH Q7的 12.8部分，“分析方法验证”。有关产品调查的指南，参见ICH Q7，6.5部分，批生产记录，6.7，批生产记录审核，8.1，生产操作和15，投诉和召回。

(b) Objective 1b: A sound and appropriate program for sampling, testing, and evaluating components (including APIs), in-process materials, finished products, containers, and closures for purposes of releasing materials or products has been established, including a robust supplier qualification program.

(b) 目标1b：对成分、中间体、成品、容器及密封件的取样，检验和评估都建立了完善的相适应的程序，以放行物料或成品，包括稳健的供应商资质认定程序。

Review sampling plans and procedures, including those described in batch records, to evaluate the establishment’s intended approach to sampling components, in-process materials, and finished product. Sampling plans must ensure that representative samples are collected and tested/examined as verification of product quality. The method of selecting samples, number of samples taken, statistical criteria for the number of samples taken, and acceptable and unacceptable quality limits should be scientifically based and appropriate. Consider the extent of experiences with the proposed commercial process when determining adequacy of sampling plans. Also, areas of criticality or process vulnerability should receive special attention because these points in a process generally require more extensive sampling. For example, a firm may consider the use of process analytical technology (PAT).

审核取样计划和程序，包括批记录中描述的相关内容，来评估企业对成分，中间体和成品的取样方式。取样计划必须能保证对样品的收集和检验/测试具有代表性，可以证明产品的质量。选择样品的方式，取样数量，取样数量的统计学标准，可接受质量限度和不可接受质量限度等内容的确定需要适当且有科学依据。当确定取样计划是否充分时应考虑到特定商业化工艺的经验程度。而且，关键区域或者工艺不稳定时应给予特殊注意，因为生产过程中这些问题的存在会需要扩大取样。例如，有的企业可能会考虑过程分析技术（Process Analytical Technology，PAT）的使用。

For finished dosage establishments purchasing multiple lots of components from an external supplier, evaluate the suppliers’ variability and the specification criteria. For finished dosage and API establishments, the firm should establish statistical criteria for component, in-process, and finished product variability in comparison with the specification criteria. If the division believes that it is warranted, a for-cause sample of the component can be collected. Contact the laboratory for instructions before collection.

对需从外部供应商处购买多种成分的制剂生产企业来说，供应商的可变性以及质量标准需要评估。制剂生产企业和API生产企业都需对成分，中间体，和成品的可变性建立统计学标准，并与规格标准进行对比。如果地区办公室确定被授权可以对成分进行有因取样，可以去收集样品。采集前请联系实验室获取指导。

Related regulations for finished pharmaceuticals: 21 CFR 211.160 requires sampling plans (and specifications) to be scientifically based and appropriate; 21 CFR 211.165 requires sampling plans for finished product to be in writing and to meet appropriate statistical quality control criteria before batch release; 21 CFR 211.110, 211.134, and 211.166 address sampling in the context of in-process materials, labeling, and stability, respectively; and 21 CFR 211.84 requires that sampling of components, drug product containers, and closures be representative.

制剂的相关法规：制剂成品相关法规：21 CFR 211.160 要求所有的取样计划（包括质量标准）是适当的并有科学依据；21 CFR 211.165要求应有书面的成品取样计划，并符合适当的统计质量控制标准，然后才可进行批放行；21 CFR 211.110, 211.134, 和 211.166 分别说明了对中间体控制，标签取样，稳定性考察等背景下的取样要求。

Related guidance for APIs: Refer to ICH Q7, section XI.A, General Controls, which recommends sampling plans to be scientifically sound and appropriate and sampling procedures to be in writing. This section also addresses sampling in the context of raw materials, intermediates, APIs, and labels and packaging materials. ICH Q7, section VII.C, Sampling and Testing of Incoming Production Materials, recommends that samples should be representative of the batch of material from which they are taken. ICH Q7, section XI.F, Expiry and Retest Dating, addresses sampling in the context of performing a retest.

API的相关指南：对API的相关指南：关于API，参见ICH Q7的11.1部分，实验室控制—— 一般控制，此部分要求所有的取样计划的科学性和适用性，而且需有书面的取样规程。这个部分也阐述了对原辅料，中间体，API，标签和包装材料不同的取样要求。ICH Q7 的7.3部分，“进厂物料的取样和检测”，要求了对整批物料的取样应具有代表性。ICH Q7 的 11.6部分，“有效期与复验期”，说明了进行复验时的取样方法。

(c) Objective 1c: Sufficient facility and equipment controls are in place to prevent contamination of and by the application product (or API).

(c) 目标 1c: 具有充分的生产设施和设备控制来防止其申报产品污染，或被污染（或API）。

Coverage of this element is warranted for new construction or facility design, new uses of existing equipment that pose potential risks (e.g., addition of a highly potent product), or equipment operations unique to the application under review. Observe the firm’s operations as you inspect the facility and after reviewing blueprints, floor plans, or as-built diagrams of utility systems (such as the purified water system piping and air handling systems). Verify that the establishment has facility, equipment cleaning, maintenance, and utility system controls in place (or planned) that are designed to prevent contamination that could be deleterious to the specific application product, and ensure that controls are in place to prevent cross-contamination of and by the application product.

对于新建工程或者厂房设计，具有潜在风险的已有设备的新使用（比如，增加一个高活性产品的生产），或者对申报产品的设备操作是独特的，将此要素包含进检查目标是很有必要的。要通过检查设施，审核蓝图，平面布局图，或公共系统竣工图（比如纯化水系统管线，和空调系统）等观察企业的运行。要证明企业设计有厂房，设备，和公共系统的控制程序来防止可能对申报产品造成的有害污染，并确保控制程序能防止申报产品造成的交叉污染或者是申报产品被交叉污染。

Inspect new construction intended for the application product, as well as the installation of new equipment, and other significant changes to the existing facility or practices relating to material/personnel flow. Evaluate the establishment’s proposed compliance with related CGMP requirements. Pay special attention to the new product or marketed products that are highly potent or potentially sensitizing in humans to ensure that the product is not liable to contaminate existing products in the facility.

检查为申报产品新建的工程，以及新安装的设备，和其他对已有厂房或物流/人流程序所作的重大变更。评估企业与相关CGMP要求的符合性。对那些高活性或者是对人体潜在致敏的产品，不论新产品或已上市产品，都要特别注意，以确保此类产品不易污染到厂房里的其他已有产品。

Related regulations for finished pharmaceuticals: 21 CFR 211.42–211.67 require facility and equipment controls to prevent contamination and to ensure well-organized operations.

制剂成品相关法规：21 CFR 211.42–211.67，要求具备厂房和设备控制程序来防止污染并保证生产有组织进行。

Related guidance for APIs: Refer to ICH Q7, sections IV.A (Design and Construction) through V.B (Equipment Maintenance and Cleaning), which recommend facility and equipment controls to prevent contamination and to ensure well-organized operations.

API的相关指南：对API的相关指南：参见ICH Q7的 从4.1部分（厂房与设施—设计与施工）到5.2部分（生产设备—设备维护与清洁），要求对厂房与设备进行控制以防止污染并保证生产有组织进行。

(d) Objective 1d: Adequate procedures exist for batch release, change control, and investigating failures, deviations, complaints, and adverse events, and for reporting this information to FDA (e.g., through FARs).

(d) 目标1d：批放行，变更控制，调查失败，偏差，投诉，不良事件等都有足够的管理程序进行控制，包括将这些信息报告给FDA的程序，比如现场警戒报告。

Review the establishment’s quality and change procedures and audit the establishment’s compliance to its procedures for already marketed product, as appropriate (e.g., selecting actual failures, deviations, and complaint investigations; related adverse drug experience reports, including submissions to FDA if required). Note that the regulations for adverse drug experience (ADE) reporting only cover prescription and application products. If significant problems are found with the establishment’s existing complaint handling and reporting procedures, the division should consider recommending a directed inspection of the ADE reporting system under compliance program 7353.001—Postmarketing Adverse Drug Experience (PADE) Reporting Inspections.

审核企业的质量和变更规程，并视情况审计在企业已上市药品的生产中，企业实际行为与其管理规程的符合性（比如，实际检验失败的样品，偏差，投诉调查，或者相关不良药物体验报告处理，包括按要求提交给FDA的信息等）。注意，适用于ADE报告的法规仅涵盖了处方药和处在申报期间的药品。如果发现企业已有的投诉处理和报告规程存在重大问题，地区办公室应考虑根据CPGM 7353.001，建议一个直接对ADE报告系统的检查。

Related regulations for finished pharmaceuticals: 21 CFR 211.192 and 211.198 address failure and complaint investigations; 21 CFR 211.100 addresses deviations from written manufacturing procedures; 21 CFR 314.81(b)(1) is the requirement for submitting a FAR to FDA; 21 CFR 314.80 addresses ADE reporting requirements for application products; and 21 CFR 310.305 addresses ADE reporting requirements for marketed prescription drugs for human use without approved NDAs.

制剂产品相关法规：21 CFR 211.192 和 211.198，失败和投诉调查；21 CFR 211.100，与已批准生产规程的偏差；21 CFR 314.81(b)(1) 提交现场警戒报告给FDA的要求。21 CFR 314.80，在申报产品提交ADE报告的要求；21 CFR 310.305 已上市人用处方药提交ADE报告的要求。

Related guidance for APIs: Refer to ICH Q7, sections VI.E, Batch Production Records, VI.G, Batch Production Record Review, VIII.A, Production Operations, and XV, Complaints and Recalls, for guidance relating to failure and complaint investigations and deviations from written manufacturing procedures.

API的相关指南：API相关指南：见ICH Q7的 6.5部分，批生产记录，6.7部分，批生产记录审查8.1部分，生产操作，15部分，投诉和召回，从中找到相关失败和投诉调查和/或与书面已批准生产规程发生偏差的相关指南。

(e) Objective 1e: The proposed commercial process and manufacturing batch record, including instructions, processing parameters, and process control measures, are feasible and scientifically and objectively justified. This objective is linked to the firm’s process validation program across the product lifecycle.

(e) 目标1e：企业准备的商业化生产工艺的可行性以及批生产记录，包括说明，工艺参数，工艺控制措施等，是科学的并经过客观评价。这个检查目标可与企业的工艺验证项目联系起来。

An essential part of the inspection is evaluating the justification for the proposed commercial process and the manufacturing batch record. The extent of process validation activities that have been completed at the time of application submission can vary, but, at a minimum, data from Stage I process validation should be available. To establish process feasibility, evaluate Stage I process validation development studies and knowledge gained about manufacturing operation vulnerabilities, including the influence of raw material variability, and determine the purpose of each study performed by the firm. For example, review studies conducted to establish process controls or process parameters directly related to the CQAs of the drug product in the application. These may include studies of worst-case or boundary conditions to establish proven acceptable ranges or more sophisticated studies involving design of experiment or multivariate analysis modeling. Assess the protocols and their execution and the reliability of the data and conclusions. Include the inadequacy of data to support the filed processing approach, or the proposed master batch record provided during inspection, on Form FDA 483.

现场检查的关键部分就是评估计划的商业化生产工艺以及批生产记录的合理性。在提交申请时已经完成的工艺验证活动的范围可以有所不同，但至少应提供来自第一阶段工艺验证的数据。为建立工艺可行性，评估第一阶段工艺验证开发研究和获得的关于生产操作高位环节的知识，包括原料变异性的影响，并确定企业每项研究的目的。比如，审核为建立与产品关键质量属性直接相关的工艺控制或工艺参数所开展的研究。这些研究可能包括“最差情况”或者边界条件研究来建立“已证明的可接受范围”，或者是更复杂的研究，包括实验设计或者多变量分析模型。然后对试验方案，试验开展，数据的可靠性和结论进行评估。若检查员在检查中发现，用来支持已备案工艺方法，或者拟议的主批记录的数据不够充分，则这种情况应被记入483。

This evaluation includes a review of the firm’s scale-up studies (e.g., the scale-up from the biobatch, or pivotal batches, to a larger (interim or full) scale batch). The firm may need to change its proposed commercial process as scale-up studies are completed and knowledge is gained. Such changes alone are not a violation and should not be cited as a deficiency. However, if feasible, discuss these findings with the OPF manufacturing assessor to determine the impact of such changes on the objectives of this compliance program.

选择并评估研发内容（比如，从生物批或者中试批向更大规模（中间规模或全规模）批次的放大）。注意，随着放大研究的完成和知识收集，企业可能需要改变已提交的计划的商业批工艺。这种变更并不是一种违规，不应视为缺陷。但是，如果可行，请与OPF生产审评员讨论这些发现，以确定此类变更对本合规计划目标的影响。

Determine and report the firm's projected timeline for completion of additional process validation activities and additional planned studies and their purpose. Though not required at the time of the PAI, completion of certain planned studies, including Stage 2 of process validation, may demonstrate that the product can be reliably manufactured at commercial scale. If the firm states that it has completed the process validation activities necessary to distribute the finished drug product (i.e., completion of Stage 2, Process Performance Qualification), fully audit and assess these studies and conclusions. These include studies and experiments to scientifically optimize processing parameters and other manufacturing instructions for significant processing steps. Additional studies typically include commercial-scale batches (conformance batches) that are manufactured at the site in accordance with the master batch and production control record using qualified commercial-scale equipment and utilities and trained production personnel. These commercial-scale studies are typically conducted in accordance with a formal protocol and are intended to confirm the process design before commercial launch. They also establish a level of reproducibility and consistency at nominal processing conditions. One of the firm’s conclusions from these Stage 2 process validation studies must be that a high level of assurance was achieved in that the commercial process is capable of consistently delivering quality product meeting its CQAs. Though not required at the time of the PAI, the manufacturer is expected to plan for sufficient ongoing evaluation (Stage 3, Continued Process Verification) of the manufacturing process once marketing approval has been granted by CDER.

检查员需进行确认并上报企业计划完成附加工艺验证和其它研究的时间和目标。虽然在PAI时不需要，某些计划的研究（包括工艺验证的第2阶段）的完成可以证明该产品可以在商业规模上可靠地生产。如果企业声明所有工艺验证活动包括商业规模确认批的生产已经完成，可满足成品销售的要求，检查员需对这些研究和结论进行全面的检查和评估。这些研究包括为科学建立合适的工艺参数及其他关键生产步骤的生产指令进行的研究与实验。附加研究一般会包含商业化规模（确认批）批次的生产，这些批次是按照主批生产和控制记录，使用经过确认的商业化规模的设备及公共系统，由经过培训的生产人员在本场地生产出来的。而且这些研究需要根据正式的方案开展，用来在商业化上市前确认工艺设计，也在预设的工艺条件下建立了一定水平的重现性和一致性。企业从这些工艺验证研究中得出的结论必须是达到了一种“高水平的保证”，保证商业化工艺有能力持续一致地生产出满足关键质量属性的合格产品。虽然在PAI时不需要，一旦产品在CDER批准上市后，生产商应当计划对生产工艺进行充分的持续评估（阶段3，持续工艺验证）。

Thoroughly examine results and data of manufactured batches to determine if unresolved issues exist with the commercial control strategy. Listed below are examples of situations requiring follow-up:

• The drug product or API does not meet its CQAs, and root cause has not been determined.
• Batch records, in-process data, or process monitoring records reveal an unexpected highly variable process and the reason is unknown.
• Inconsistent execution of the batch record and manufacturing instructions or operator workarounds (possible indication of poor process design or training).
• Control measures do not appear to align with raw development data (e.g., important parameters or material attributes that impact CQAs are not being monitored or measured at the appropriate frequency).
• Sampling and monitoring plans for Stage 2 process validation (e.g., process qualification) are not justified or are insufficient based on raw development data.
• The data justifying critical process parameters are inadequate.

对生产批次的结果和数据进行彻底检查，以确定商业化控制策略是否存在未解决的问题。以下是需要跟进的情况示例：

• 制剂或者API未能达到其关键质量属性，且其根本原因未找出；
• 批记录，中间数据和/或工艺监控记录显示出一种预期外的大幅的工艺变动，但原因未知；
• 实际操作不符合批记录及生产指令和/或操作者“另辟蹊径”（可能预示着不良的工艺设计或培训）；
• 控制措施似乎不符合原始研发数据（例如，影响CQA的重要参数或物料属性没有以适当频率监测或测量）。
• 第2阶段工艺验证（例如，工艺确认）的取样和监控计划没有依据原始研发数据来论证或不充分。
• 证明关键工艺参数的数据是不充分的。

Review completed studies in the process validation lifecycle for related drugs to evaluate the firm’s capabilities and procedures. Interviewing key employees, such as the lead validation engineer, may be helpful in assessing a firm's ability to implement a sound process and control strategy. List deficiencies in these studies on Form FDA 483, and advise the firm that appropriate corrections must be completed before commercial distribution of the first batch.

审核相关药品工艺验证生命周期的已完成研究，以评估企业的能力和规程。与关键员工进行交谈，比如首要验证工程师，可以起到帮助评估企业是否有能力实施健全的工艺与控制策略。在FDA 483表中列出这些研究中的缺陷，并告知企业必须在商业化分销第一批之前完成适当的纠正措施。

If unable to provide sufficient process validation lifecycle coverage, state as such in the inspection report. Divisions should cover these processes during the next surveillance or postapproval inspection.

如果无法覆盖足够的工艺验证生命周期，请在检查报告中说明。地区办公室将在后续的常规监督检查或批准后检查中涵盖这些内容。

ORA and CDER review of information may overlap because applicants are being encouraged to share more product and process development information with CDER in accordance with FDA guidance. The investigator should incorporate CDER insights into the inspectional evaluation of the proposed commercial process and should discuss inspectional findings regarding the adequacy of the establishment’s Stage 2 process validation plans (i.e., process performance qualification plans) with OPF. The investigator should discuss process performance qualification plan issues with the firm, document the discussion in the EIR for CDER review, and, when applicable, document pertinent observations on Form FDA 483.

ORA和CDER对信息的审核可能会重叠，因为鼓励申请者根据FDA指南与CDER共享更多的产品和工艺开发信息。检查员应将CDER见解纳入对拟上市商业化工艺的检查评估中，并应讨论检查结果，并与OPF讨论关于企业2级工艺验证计划（即工艺性能确认计划）的充分性。检查员应与企业就验证计划存在的问题进行讨论，并将讨论内容记录在EIR中方便CDER查阅，并在适当时记入483。

OPQ requires that certain data be filed to demonstrate that aseptic filling and sterilization processes are validated before approval is granted. OPF’s review of this summary information is complemented by FDA’s on-site inspection of these operations. Evaluating the adequacy of process validation at a facility is critical to ensure implementation of reproducible processes.

药品质量办公室要求某些特殊数据的申报，以证明无菌灌装工艺和灭菌工艺在产品批准前完成了验证。对这些概述性信息的审核需要FDA现场检查的支持。在生产现场对工艺验证充分性进行评估对于保证工艺重现性来说很关键。

The investigator may find that the inspected establishment was not responsible for performing some of the process development activities and studies, and that reports for development studies are not available for inspection. The investigator should collect information about each establishment involved in process development (e.g., name, address, responsible person, work performed). This information should be included in the EIR. The OPF manufacturing assessor will then determine if additional facilities need to be evaluated or inspected.

检查员可能会发现被检查企业不负责执行某些工艺开发活动和研究，并且开发研究的报告不可用于检查。检查员应收集所有涉及到工艺开发的企业信息，比如企业名称，地址，负责人，各自开展的工作。这些信息应写入EIR。然后，OPF生产审评员会确定是否需要对额外的设施进行评估或检查。

Related regulations for finished pharmaceuticals: 21 CFR 211.100(a) and 211.110 require developing a well-designed and reproducible process, and 21 CFR 211.22 covers the quality unit’s responsibilities. Aseptic and sterilization processes are required to be validated by 21 CFR 211.113(b) and 211.42.

制剂产品相关法规：21 CFR 211.100(a) 和 211.110 要求开发设计良好的可重现的工艺；21 CFR 211.22 中描述了质量部门的责任。21 CFR 211.113(b) 和 211.42 中描述了无菌和灭菌工艺的验证的要求。

Related guidance for APIs: Refer to ICH Q7, sections XII.A (Validation Policy) through XII.E (Process Validation Program) for guidance regarding process validation.

API相关指南：工艺验证相关指南见ICH Q7的 12.1（验证方针）到12.5（工艺验证程序） 部分 。

作者：识林-枫
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参考资料
[1] FDA CPGM 7346.832 Pre-Approval Inspections-Investigations 2019/08/13